Cardioprotective Effects of PDE-5 Inhibitors

PDE-5 抑制剂的心脏保护作用

基本信息

批准号：
7790958
负责人：
Rakesh C Kukreja
金额：
$ 44.85万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7790958
关键词：
Adenosine Animal Model Animals Apoptosis Apoptotic Atherosclerosis Attenuated Bayer brand of vardenafil hydrochloride Biological Availability Blood Vessels Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Death Cell model Chronic Cialis Clinical Trials Cyclic GMP Cyclic GMP-Dependent Protein Kinases DNA Binding Development Diabetic mouse Doxorubicin Endothelium Erectile dysfunction Fasting Functional disorder Gene Expression Gene Transfer Generations Glucose Guanylate Cyclase Heart Heart Hypertrophy Heart failure Human Hydrolysis Hyperglycemia Impairment Injury Insulin Insulin Resistance Investigation Ischemic Preconditioning Knowledge Lead MAPK8 gene Mediator of activation protein Metabolic Diseases Molecular Mus Muscle Myocardial Infarction NADPH Oxidase Nitric Oxide Nitric Oxide Signaling Pathway Non-Insulin-Dependent Diabetes Mellitus Obesity Oryctolagus cuniculus Oxidative Stress Oxis Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Population Process Production Pulmonary Edema Reperfusion Injury Role Sclerosis Signal Pathway Signal Transduction Sildenafil citrate Soluble Guanylate Cyclase Tenuate Testing Therapeutic Effect Vasodilation Viagra Xanthine Oxidase Xanthines acute coronary syndrome base cardiovascular risk factor cytokine db/db mouse diabetic diabetic cardiomyopathy diabetic patient glucose uptake improved in vivo inhibitor/antagonist innovation insight men mitochondrial K(ATP) channel nitrosative stress novel overexpression phosphodiesterase V prevent protective effect public health relevance receptor-mediated signaling sildenafil tadalafil tool vardenafil

项目摘要

DESCRIPTION (provided by applicant): Our innovative studies during the past 7 years have shown that potent phosphodiesterase-5 (PDE-5) inhibitors including sildenafil citrate (Viagra(R)) induce powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in various animal and cellular models. The purpose of this competing renewal application is to further demonstrate the therapeutic effect of these drugs against myocardial infarction (MI)-induced heart failure and insulin resistance in diabetic mice. We will test the following new hypotheses: 1: Modulation of cGMP with PDE-5 inhibitors and novel soluble guanylate cyclase (sGC) activator protect against myocardial infarction, apoptosis, remodeling and insulin resistance in the db/db diabetic mouse. We will determine the efficacy of short acting (sildenafil) or long acting (tadalafil) PDE-5 inhibitors and a novel sGC activator, BAY 58-2667 in protecting the diabetic heart and cardiomyocytes against myocardial infarction, apoptosis, contractile dysfunction, cardiac hypertrophy, pulmonary edema following I/R injury. 2: PDE-5 inhibitors/ sGC activator decrease oxidative stress and attenuate the expression of proinflammatory cytokines post MI in diabetic mice. 3: cGMP dependent protein kinases PKGI1 and 2 directly protect the diabetic heart through signaling mechanism involving activation of PI3K/Akt, AMPK, and inhibition of JNK and GSK- 32. These studies will be the first to demonstrate the protective effect of PDE-5 inhibitors and novel sGC activator in protection against post MI-induced heart failure in diabetic mice. We anticipate that results of these investigations will provide novel insights into expanding the utility of the cGMP preserving/generating compounds for treatment of diabetic cardiomyopathy. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are two of the most prevalent metabolic disorders in the world. Type II diabetes is associated with insulin resistance and increased myocardial infarction in both animal models and patients. In this proposal, we will study a new strategy for the protection of the heart and treatment of insulin resistance in Type II diabetic mice with erectile dysfunction drugs (Viagra(R) and Cialis(R)) and a novel drug BAY 58 2667 which produces cGMP - a potent muscle relaxing molecule in the body. We believe that knowledge derived from these studies will provide additional tools to the cardiologists in reducing damage of the heart following a heart attack and treatment of heart failure in diabetic patients. Moreover, our studies will help understand the molecular basis of the protection with these drugs.

描述（由申请人提供）：我们过去 7 年的创新研究表明，包括柠檬酸西地那非 (Viagra(R)) 在内的强效磷酸二酯酶 5 (PDE-5) 抑制剂可针对缺血再灌注损伤 (I/R) 产生强大的心脏保护作用）在各种动物和细胞模型中。此次竞争性更新申请的目的是进一步证明这些药物对糖尿病小鼠心肌梗塞（MI）诱发的心力衰竭和胰岛素抵抗的治疗效果。我们将测试以下新假设： 1：用 PDE-5 抑制剂和新型可溶性鸟苷酸环化酶 (sGC) 激活剂调节 cGMP 可保护 db/db 糖尿病小鼠免受心肌梗塞、细胞凋亡、重塑和胰岛素抵抗。我们将确定短效（西地那非）或长效（他达拉非）PDE-5 抑制剂和新型 sGC 激活剂 BAY 58-2667 在保护糖尿病心脏和心肌细胞免受心肌梗塞、细胞凋亡、收缩功能障碍、心脏肥大、 I/R 损伤后发生肺水肿。图 2：PDE-5 抑制剂/ sGC 激活剂可减少糖尿病小鼠的氧化应激并减弱 MI 后促炎细胞因子的表达。图 3：cGMP 依赖性蛋白激酶 PKGI1 和 2 通过涉及激活 PI3K/Akt、AMPK 以及抑制 JNK 和 GSK-32 的信号传导机制直接保护糖尿病心脏。这些研究将首次证明 PDE-5 的保护作用抑制剂和新型 sGC 激活剂可预防糖尿病小鼠心肌梗死后诱发的心力衰竭。我们预计这些研究的结果将为扩大 cGMP 保存/生成化合物在糖尿病心肌病治疗中的应用提供新的见解。公共卫生相关性：肥胖和 2 型糖尿病是世界上最普遍的两种代谢性疾病。 II 型糖尿病与动物模型和患者的胰岛素抵抗和心肌梗塞增加有关。在本提案中，我们将研究一种使用勃起功能障碍药物（伟哥（R）和西力士（R））保护II型糖尿病小鼠心脏和治疗胰岛素抵抗的新策略以及一种新药BAY 58 2667，该药物产生cGMP - 体内一种有效的肌肉放松分子。我们相信，从这些研究中获得的知识将为心脏病专家提供额外的工具，以减少心脏病发作后的心脏损伤和治疗糖尿病患者的心力衰竭。此外，我们的研究将有助于了解这些药物保护的分子基础。